Divergent Pd-Catalyzed and Radical Cyclizations of Nucleophilic

Divergent Pd-Catalyzed and Radical Cyclizations of Nucleophilic Cyclic Enamines Derived from Functionalized Amine and Aldehyde Fragments

SCHEME 1. Formation of Tetrahydropyridines from Amines and Aldehydes

Jose´ M. Aurrecoechea,* Carlos A. Coy,† and Oscar J. Patin˜o† Departamento de Quı´mica Orga´nica II, Facultad de Ciencia y Tecnologı´a, UniVersidad del Paı´s Vasco, Apartado 644, 48080 Bilbao, Spain

SCHEME 2.

Strategy to Polycyclic Building Blocks 7 and 8

[email protected] ReceiVed March 18, 2008

Tetrahydropyridines carrying pendant halide functionality at the enamine β-carbon have been prepared by condensation between appropriately functionalized aldehydes and a vinylogous Mannich adduct. Those enamines display divergent behavior in radical and Heck reactions. Thus, radical addition takes place in a 5-exo-trig fashion whereas Heck couplings follow a 6-endo-trig pathway. The resulting polycyclic products are obtained with high regio- and stereoselectivity. The condensation between vinylogous Mannich adducts 1 and aldehydes 2 leads to cyclic enamines 3 (Scheme 1), and this reaction has found recent use in the preparation of polysubstituted piperidine derivatives via hydrogenation reactions as well as nucleophilic addition- and reductive-type couplings.1 Appropriately substituted tetrahydropyridines 4 could in principle be envisaged as precursors of polycyclic systems 7 and/or 8 via intramolecular radical-2 or Heck-type3 additions †

Present address: Departamento de Quı´mica, Facultad de Ciencias, Universidad Nacional de Colombia, Bogota´ D.C., Colombia. (1) (a) Aurrecoechea, J. M.; Gorgojo, J. M.; Saornil, C. J. Org. Chem. 2005, 70, 9640–9643. (b) Aurrecoechea, J. M.; Suero, R.; de Torres, E. J. Org. Chem. 2006, 71, 8767–8778. (2) Reviews: (a) Parsons, A. F. C. R. Acad. Sci., Ser. II 2001, 4, 391–400. (b) Clark, A. J. Chem. Soc. ReV. 2002, 31, 1–12. (c) Bowman, W. R.; Fletcher, A. J.; Potts, G. B. S. J. Chem. Soc., Perkin Trans 1 2002, 2747–2762. (d) Ishibashi, H.; Sato, T.; Ikeda, M. Synthesis 2002, 695–713. (e) Majumdar, K. C.; Basu, P. K.; Mukhopadhyay, P. P. Tetrahedron 2005, 61, 10603–10642. (3) Reviews: (a) Beletskaya, I. P.; Cheprakov, A. V. Chem. ReV. 2000, 100, 3009–3066. (b) Larhed, M.; Hallberg, A. In Handbook of Organopalladium Chemistry for Organic Synthesis; Negishi, E. Ed.; Wiley and Sons: New York, 2002; Vol. 1, pp 1133-1178. (c) Braese, S.; de Meijere, A. In Metal-Catalyzed Cross-Coupling Reactions, 2nd ed.; de Meijere, A., Diederich, F. Eds.; WileyVCH: Weinheim, Germany, 2004; Vol. 1, pp 217-315.

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to the enamine double bond through intermediates 5 and 6, respectively (Scheme 2). Compounds with general structures 7 and 8 are interesting as functionalized building blocks because their respective azaspirocyclic and tricyclic benzo[h]quinoline basic skeletons are found in a number of biologically active products.4 A condensation/cyclization approach to these compounds (Schemes 1 and 2) would be attractive because of its simplicity, conciseness, and flexibility to introduce precursors for various types of C-radicals and Pd-complexes through simple aldehydes 2. Furthermore, because R, R1, and R3 are necessarily alkyl groups in 3 and 4, these cyclizations would involve nucleophilic cyclic enamine intermediates of the general types represented by 9 and 10, which have seldom been reported except for indole-type enamines.5,6 Moreover, in the case of radicals 9, the cyclizations are poorly regioselective5b unless additional activation is provided at the enamine R-position.5a (4) See: (a) Khan, F. A.; Dash, J. J. Org. Chem. 2003, 68, 4556–4559. (b) McManus, A. H.; Fleming, M. J.; Lautens, M. Angew. Chem., Int. Ed. 2007, 46, 433–436. (c) Harrison, T. J.; Patrick, B. O.; Dake, G. R. Org. Lett. 2007, 9, 367–370, and references cited therein. (5) Radical reactions of type 9 with indole derivatives: (a) Yang, C. C.; Chang, H. T.; Fang, J. M. J. Org. Chem. 1993, 58, 3100-3105. (b) Flanagan, S. R.; Harrowven, D. C.; Bradley, M. Tetrahedron Lett. 2003, 44, 1795-1798 and references cited therein. For reactions involving N-sulfonyl- or N-methoxycarbonyl enamines, see:(c) Ahman, J.; Somfai, P. J. Chem. Soc., Perkin Trans. 1 1994, 1079–82. (d) Parsons, P. J.; Penkett, C. S.; Cramp, M. C.; West, R. I.; Warrington, J.; Saraiva, M. C. Synlett 1995, Sp. Iss., 507–509. (e) Parsons, P. J.; Penkett, C. S.; Cramp, M. C.; West, R. I.; Warren, E. S. Tetrahedron 1996, 52, 647–60. (6) Heck reaction of type 10 with indole derivatives: (a) Joucla, L.; Putey, A.; Joseph, B. Tetrahedron Lett. 2005, 46, 8177–8179. (b) Avila-Zarraga, J. G.; Lujan-Montelongo, A.; Covarrubias-Zuniga, A.; Romero-Ortega, M. Tetrahedron Lett. 2006, 47, 7987–7989.

10.1021/jo800619m CCC: $40.75  2008 American Chemical Society Published on Web 06/05/2008

TABLE 1.

Preparation of Tetrahydropyridines 12

Therefore, the possibility of using tetrahydropyridines of type 4 appeared to be worth exploring since this would provide an opportunity to further examine the radical and Pd-catalyzed chemistry of the enamine functional group. In this paper we report an expeditious and divergent approach to building blocks of general types 7 and 8 through a common tetrahydropyridine 4 utilizing highly regio- and stereoselective 5-exo-trig radical additions and 6-endo-trig Heck couplings, respectively.7 Amine 111b,8 and aldehydes 2a-d were selected as precursors of representative substrates for radical and Pd-catalyzed reactions. The choice of amine 11 as a convenient starting material was dictated by its ready availability in multigram quantities.1b Aldehydes 2a-c were known compounds,9 while the preparation of 2d followed the procedure reported for 2c.9c Tetrahydropyridines 12a-d were then prepared by condensation between 11 and 2a-d in CH2Cl2 at room temperature with the yields indicated in Table 1. Enamines 12 were conveniently purified by column chromatography and could be stored for several days without appreciable degradation, with the exception of 12a, which underwent self-decomposition on standing at room temperature and had to be used soon after purification. This is not completely surprising since 12a holds at the same time a nucleophilic enamine and an alkylating agent. In any case, it is remarkable that reaction conditions are mild enough to allow the preparation of this type of compound. Treatment of tetrahydropyridines 12 under typical radical cyclization conditions with (TMS)3SiH/AIBN in toluene at 100 (7) Related 6-endo-trig radical and 6-exo-trig Pd-catalyzed reactions have been reported for enamide-type systems with the cyclizing chain attached to the enamide R-carbon. Radical: (a) Ripa, L.; Hallberg, A. J. Org. Chem. 1998, 63, 84–91. Pd-catalyzed: (b) Ripa, L.; Hallberg, A. J. Org. Chem. 1996, 61, 7147– 7155. (c) Ripa, L.; Hallberg, A. J. Org. Chem. 1997, 62, 595–602. (d) Lindstrom, S.; Ripa, L.; Hallberg, A. Org. Lett. 2000, 2, 2291–2293. (8) Ha, H.-J.; Kang, K.-H.; Ahn, Y.-G.; Oh, S.-J. Heterocycles 1997, 45, 277–286. (9) (a) Hon, Y. S.; Chang, F. J.; Lu, L.; Lin, W. C. Tetrahedron 1998, 54, 5233–5246. (b) Brebion, F.; Vitale, M.; Fensterbank, L.; Malacria, M. Tetrahedron: Asymmetry 2003, 14, 2889–2896. (c) Gibson, S. E.; Jones, J. O.; McCague, R.; Tozer, M. J.; Whitcombe, N. J. Synlett 1999, Sp. Iss., 954–956.

TABLE 2.

a

Radical Cyclizations of Enamines 12

Ratio of 13 to an undetermined mixture of isomers.

°C resulted in the formation of spirocycles 13 in good yields (Table 2). Products derived from alkyl (entry 1), vinyl (entry 2), or aryl (entries 3 and 4) radicals are all effectively obtained in a highly regio- and stereoselective fashion, with the alternative regioisomers 14 and/or stereoisomers being formed in only minor amounts. In the reaction of 12b a furoquinoline derivative of type 14 was clearly identified by comparison of diagnostic 13C NMR signals with those of the spiro derivative 13b. Thus, a CH2 unit and the characteristic spirocyclic quaternary carbon of 13b were replaced by two CH carbons in the corresponding regioisomer. As expected, the major stereoisomer in these reactions was formed by radical addition to the less congested face of the enamine double bond, i.e., anti to the fused lactone moiety. This was determined for 13b-d by the observation of NOE’s between the lactone bridgehead protons and either one vinylic hydrogen (in the case of 13b) or the aromatic o-H proximal to the spirocyclic quaternary carbon (in the case of 13c and 13d). The cyclizations depicted in Table 2 represent an unusual type involving the addition of a nucleophilic C-radical to an electron-rich enamine double bond. This polarity mismatch has been shown to retard the rate of addition of nucleophilic C-radicals to enamines,10 and as a result, intermolecular reactions have mainly employed electrophilic radicals containing (10) Giese, B. Angew. Chem., Int. Ed. Engl. 1983, 22, 753–764. (11) (a) Renaud, P.; Schubert, S. Angew. Chem., Int. Ed. Engl. 1990, 29, 433–434. (b) Renaud, P.; Schubert, S. Synlett 1990, 624–626. (c) Russell, G. A.; Wang, K. J. Org. Chem. 1991, 56, 3475–3479. (d) Curran, D. P.; Thoma, G. J. Am. Chem. Soc. 1992, 114, 4436–4437. (e) Renaud, P.; Bjo¨rup, P.; Carrupt, P. A.; Schenk, K.; Schubert, S. Synlett 1992, 211–213. (f) Schubert, S.; Renaud, P.; Carrupt, P. A.; Schenk, K. HelV. Chim. Acta 1993, 76, 2473–2489. (g) Chuang, C.-P.; Wu, Y.-L. Tetrahedron 2004, 60, 1841–1847. (h) Tsai, A.-I.; Chuang, C.-P. Tetrahedron 2006, 62, 2235–2239.

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electron-withdrawing groups,11 while the corresponding intramolecular reactions5,12 have been mostly limited to indole derivatives5,12e and to enamines with additional activation provided by aryl groups.12b–d Alternatively, the less nucleophilic, as well as more stable and easier to handle, enamide-type systems have been widely employed in a variety of synthetic applications.2 In fact, the reactions reported here appear to be the first examples of 5-exo-trig radical cyclizations of systems of type 9 (R ) alkyl) not involving indole derivatives. The regiochemistry of these radical cyclizations follows the trends observed with typical hex-5-enyl radicals, which are known to cyclize with high 5-exo-trig selectivity.13,14 In addition, in this particular case, the observed 5-exo-trig mode of addition is also consistent with the tendency displayed by intermolecular radical additions to unconstrained enamines, where the regiochemistry appears to be governed by the preservation of conjugation. As a result, addition takes place at the enamine β-carbon with formation of a relatively stable R-aminoalkyl radical.11 However, 5-exo to 6-endo cyclization ratios have also been found to be very dependent on the extent of steric congestion around the alkene terminus. For example, for simple model systems, the ratio 5-exo/6-endo goes from nearly 50:1 in the unsubstituted hex-5-enyl radical to approximately 1:2 in the 5-methylhex-5-enyl case.13,14 Therefore, in the cyclizations of sterically encumbered enamines 12 the driving force provided by the formation of an R-aminoradical 15 is remarkable, particularly in the more substituted cases of 12b-d.

The reactivity of enamines 12c,d under typical Heck conditions was examined next. Ample precedent existed on the use of enamides, formamidines, enaminones, enaminoesters, dehydroaminoesters, pyrroles, and indoles, which have all been extensively utilized in intramolecular Heck reactions.3,6,15 However, reports on the alternative use of simple enamines are very scarce and, in any case, restricted to 5-endo additions at the enamine β-position.15c,16 After some experimentation, conditions which led efficiently to intramolecular arylation products were found (Scheme 3). The major products 16 displayed an alkene moiety exocyclic to the piperidine ring, and were accompanied by minor amounts of double bond isomerization products 17. The use of TlOAc as additive was found to be important to minimize this isomerization,7b,c,17 as shown by the increased amount of 17c (16c/17c ) 1.4:1, 52%) obtained when TlOAc was replaced by KOAc under otherwise similar conditions. Additionally, a significantly higher efficiency was noticed (12) (a) Glover, S. A.; Warkentin, J. J. Org. Chem. 1993, 58, 2115–2121. (b) Cladingboel, D. E.; Parson, P. J. J. Chem. Soc., Chem. Commun. 1990, 1543– 1544. (c) Ozlu, Y.; Cladingboel, D. E.; Parsons, P. J. Synlett 1993, 357–358. (d) Oezlue, Y.; Cladingboel, D. E.; Parsons, P. J. Tetrahedron 1994, 50, 2183– 2206. (e) Tanino, H.; Fukuishi, K.; Ushiyama, M.; Okada, K. Tetrahedron 2004, 60, 3273–3282. (13) Beckwith, A. L. J.; Schiesser, C. H. Tetrahedron 1985, 41, 3925–3941. (14) Beckwith, A. L. J. Chem. Soc. ReV. 1993, 22, 143–151. (15) Recent examples: (a) Sorensen, U. S.; Pombo-Villar, E. HelV. Chim. Acta 2004, 87, 82–89. (b) Wu, X.; Nilsson, P.; Larhed, M. J. Org. Chem. 2005, 70, 346–349. (c) Lachance, N.; April, M.; Joly, M.-A. Synthesis 2005, 2571– 2577. (d) Michael, J. P.; de Koning, C. B.; Mudzunga, T. T.; Petersen, R. L. Synlett 2006, 3284–3288. (16) Ackermann, L.; Althammer, A. Synlett 2006, 3125–3129. (17) Cabri, W.; Candiani, I. Acc. Chem. Res. 1995, 28, 2–7.

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SCHEME 3.

Heck Reactions of Tetrahydropyridines 12

in the reaction of electron-rich-substituted phenyl derivative 12d, and this could also be related to the use of that halide-scavenger additive.17 Thus, in the presence of Tl(I) a cationic pathway is presumably involved17 and, in that case, addition of the electronrich aryl group to the more electron-deficient R-carbon is expected to be particularly favorable.18 Formation of both 16 and 17 took place with very high stereoselectivity since no other stereoisomers were found. The stereochemistry of 16 and 17 was unambiguously established by NOE experiments and is consistent with a reaction course involving carbopalladation from the less hindered face of the enamine double bond, followed by β-H elimination with the exocyclic methylene unit. In conclusion, starting from readily available aldehydes 2 and amine 11, the tactical combination of a condensation step and either a radical- or Heck-type ring-closure provides a rapid buildup of molecular complexity in a regiodivergent and very stereoselective manner. The different regiochemistries displayed by the radical and Pd-catalyzed reactions make the two methods complementary, a feature also recognized in earlier work.7 Additionally, the presence of a lactone ring in 13 and 16 is particularly convenient as it offers further possibilities for structural diversification.1b It is noted, however, that simpler tetrahydropyridines 3 (EWG ) CO2Et) are similarly available from acyclic R,β-unsaturated esters.1a All of these combined features contribute to make the methodology appealing for the preparation of structurally diverse families of polycylic nitrogen heterocycles. Experimental Section General Procedure for the Preparation of Tetrahydropyridines 12. In a typical experiment, to a solution of amine 111b,8 (0.402 g, 1.98 mmol) and the appropriate aldehyde 2 in CH2Cl2 (24 mL) was added powdered 4 Å molecular sieves (4.0 g), and the resulting suspension was stirred at room temperature for 14 h. The mixture was filtered over Celite and the solid was washed with CH2Cl2 (3 × 15 mL). Evaporation of the combined filtrates afforded an oil that was purified by flash chromatography (silica gel saturated with Et3N) under the conditions indicated in the Supporting Information for the individual cases. General Procedure for Radical Cyclizations of Tetrahydropyridines 12: Preparation of Azaspirocycles 13. In a typical experiment, a solution of 12 (1.0 mmol), AIBN (0.164 g, 0.30 mmol), and (TMS)3SiH (616 µL, 2.0 mmol) in toluene (10 mL) was heated at 100 °C (oil bath temperature) for 16 h under Ar. After cooling, the mixture was either diluted with EtOAc (15 mL) and extracted with 1 M HCl (4 × 20 mL) (in the case of 12a and 12b) or, alternatively, evaporated to dryness, then the resulting residue was redissolved in EtOAc (20 mL) and extracted with 1 M HCl (3 × 15 mL) (in the case of 12c and 12d). In either case, the acidic extracts were basified with saturated NaHCO3 to pH 8, the solution was extracted with CH2Cl2 (3 × 25 mL), and the organic extracts were washed with brine (10 mL) and dried (Na2SO4). The residue after evaporation was purified by flash chromatography (silica gel saturated with Et3N) under the conditions indicated in the Supporting Information for the individual cases.

General Procedure for Heck Cyclizations of Tetrahydropyridines 12: Preparation of Tetracycles 16 and 17. In a typical experiment, a solution of 12 (0.50 mmol), Pd(OAc)2 (5.61 mg, 0.025 mmol), o-tolylphosphine (0.015 g, 0.050 mmol), and thalium acetate (0.145 g, 0.55 mmol) in DMF (6.0 mL) was stirred at 120 °C (oil bath temperature) for 3.5-6 h under Ar. After cooling, the solvent was evaporated and the remaining solid was purified by flash chromatography (silica gel saturated with Et3N) under the conditions indicated in the Supporting Information for the individual cases.

Supporting Information Available: Characterization data, stereochemical elucidation details, and copies of 1H NMR spectra for all new compounds. This material is available free of charge via the Internet at http://pubs.acs.org.

Acknowledgment. We thank the Spanish Ministerio de Ciencia y Tecnologı´a (Grant CTQ2004-04901, FEDER) for financial support. C.A.C. and O.J.P. also wish to acknowledge Colciencias and Universidad Nacional de Colombia for a Fellowship during their stay at UPV.

(18) (a) Vallin, K. S. A.; Zhang, Q.; Larhed, M.; Curran, D. P.; Hallberg, A. J. Org. Chem. 2003, 68, 6639–6645. (b) Andappan, M. M. S.; Nilsson, P.; Von Schenck, H.; Larhed, M. J. Org. Chem. 2004, 69, 5212–5218. (c) Mo, J.; Xu, L.; Xiao, J. J. Am. Chem. Soc. 2005, 127, 751–760. (d) Mo, J.; Liu, S.; Xiao, J. M. Tetrahedron 2005, 61, 9902-9907 See also:(e) Deeth, R. J.; Smith, A.; Brown, J. M. J. Am. Chem. Soc. 2004, 126, 7144–7151. We thank a referee for calling this work to our attention.

JO800619M

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